tbuckley/cabot-search huggingface dataset:
Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia
Authors: Ernest Moles, Christopher B. Howard, Pie Huda, Mawar Karsa, Hannah McCalmont, Kathleen Kimpton, Alastair Duly, Yongjuan Chen, Yizhou Huang, Melinda L. Tursky, David Ma, Sonia Bustamante, Russell Pickford, Patrick Connerty, Sofia Omari, Christopher J. Jolly, Swapna Joshi, Sylvie Shen, John E. Pimanda, Alla Dolnikov, Laurence C. Cheung, Rishi S. Kotecha, Murray D. Norris, Michelle Haber, Charles E. de Bock, Klaartje Somers, Richard B. Lock, Kristofer J. Thurecht, Maria Kavallaris
Journal: Science Translational Medicine (2023)

High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a “mix-and-match” principle where BsAbs were selected on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia.
Patient safety in prisons: a multi-method analysis of reported incidents in England
Authors: Isobel J McFadzean, Kate Davies, Thomas Purchase, Adrian Edwards, Stuart Hellard, Darren M Ashcroft, Anthony J Avery, Sandra Flynn, Tom Hewson, Melanie Jordan, Richard Keers, Maria Panagioti, Verity Wainwright, Florian Walter, Jenny Shaw, Andrew Carson-Stevens
Journal: Journal of the Royal Society of Medicine (2023)

Objectives Prisoners use healthcare services three times more frequently than the general population with poorer health outcomes. Their distinct healthcare needs often pose challenges to safe healthcare provision. This study aimed to characterise patient safety incidents reported in prisons to guide practice improvement and identify health policy priorities. Design: We carried out an exploratory multi-method analysis of anonymised safety incidents from prisons. Setting Safety incidents had been reported to the National Reporting and Learning System by prisons in England between April 2018 and March 2019. Participants Reports were reviewed to identify any unintended or unexpected incident(s) which could have, or did, lead to harm for prisoners receiving healthcare. Main outcome measures Free-text descriptions were examined to identify the type and nature of safety incidents, their outcomes and harm severity. Analysis was contextualised with subject experts through structured workshops to explain relationships between the most common incidents and contributory factors. Results Of 4112 reports, the most frequently observed incidents were medication-related (n = 1167, 33%), specifically whilst administering medications (n = 626, 54%). Next, were access-related (n = 559,15%), inclusive of delays in patients accessing healthcare professionals (n = 236, 42%) and managing medical appointments (n = 171, 31%). The workshops contextualised incidents involving contributing factors (n = 1529, 28%) into three key themes, namely healthcare access, continuity of care and the balance between prison and healthcare priorities. Conclusions This study highlights the importance of improving medication safety and access to healthcare services for prisoners. We recommend staffing level reviews to ensure healthcare appointments are attended, and to review procedures for handling missed appointments, communication during patient transfers and medication prescribing.
Case 15-2023: A 33-Year-Old Man with Paresthesia of the Arms and Legs
Authors: William P. Schmitt, Saurabh Rohatgi, Marcelo Matiello
Journal: New England Journal of Medicine (2023)

A 33-year-old man was evaluated for progressively worsening paresthesia in the arms and legs. Sensation was reduced in the arms and legs, and reflexes were absent in the legs. A diagnostic test was performed.
Transcatheter Therapy for Tricuspid Regurgitation — First Act
Authors: Mathias Orban, Steffen Massberg
Journal: New England Journal of Medicine (2023)

Severe tricuspid regurgitation is associated with impaired quality of life and poor survival.1 The condition is managed medically with diuretic agents; surgery is of limited use, since many patients have a variety of coexisting conditions that increase surgical risk. Current U.S. and European society guidelines recommend tricuspid-valve surgery primarily in conjunction with left heart surgery or in symptomatic patients with severe tricuspid regurgitation and right ventricular dilatation who do not have severe right ventricular dysfunction.2,3 Whether the available treatment options improve the prognosis of patients with severe isolated tricuspid regurgitation has not been addressed specifically in randomized trials. As a . . .
Emodepside — A Promising Drug for the Treatment of Soil-Transmitted Helminthiases
Authors: Antonio Montresor, Albis Francesco Gabrielli
Journal: New England Journal of Medicine (2023)

In this issue of the Journal, Mrimi and colleagues1 report the results of a trial examining the efficacy of emodepside — a drug currently used in veterinary medicine — for the treatment of Trichuris trichiura and hookworm infections in humans. Soil-transmitted helminths are a group of parasites that include Ascaris lumbricoides, T. trichiura, and hookworm (Ancylostoma duodenale and Necator americanus). These parasites cause clinically relevant impairment of nutritional status,2 notably in preschool-age children, school-age children, and women of reproductive age. To address this burden, interventions that are based on preventive chemotherapy have been implemented for more than 20 years.3 These . . .
Reinforcing the Checkpoint in Rheumatoid Arthritis
Authors: Ellen M. Gravallese, Ranjeny Thomas
Journal: New England Journal of Medicine (2023)

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor in lymphocyte activation, acting as an immune checkpoint to prevent the continued activation of T cells after an immune response and to maintain peripheral immune tolerance. PD-1 is a marker of antigen-experienced T cells. With sustained T-cell stimulation — as occurs in tumor microenvironments — PD-1 is expressed by anergic and regulatory CD4+ T cells and by exhausted CD8+ T cells. The expression of PD-1 by helper T cells is necessary for their functional interaction with B cells.1 In this issue of the Journal,2 Tuttle and colleagues report findings . . .
Testing for <i>ESR1</i> Mutations to Guide Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update
Authors: Harold J. Burstein, Angela DeMichele, Mark R. Somerfield, N. Lynn Henry
Journal: Journal of Clinical Oncology (2023)

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1andAppendix 2, online only).
At-Home Use of a Pregnancy-Specific Zone-MPC Closed-Loop System for Pregnancies Complicated by Type 1 Diabetes: A Single-Arm, Observational Multicenter Study
Authors: Carol J. Levy, Yogish C. Kudva, Basak Ozaslan, Kristin Castorino, Grenye O’Malley, Ravinder Jeet Kaur, Camilla M. Levister, Mei Mei Church, Donna Desjardins, Shelly McCrady-Spitzer, Selassie Ogyaadu, Mari Charisse Trinidad, Corey Reid, Shafaq Rizvi, Sunil Deshpande, Isabella Zaniletti, Walter K. Kremers, Jordan E. Pinsker, Francis J. Doyle, Eyal Dassau
Journal: Diabetes Care (2023)

OBJECTIVE There are no commercially available hybrid closed-loop insulin delivery systems customized to achieve pregnancy-specific glucose targets in the U.S. This study aimed to evaluate the feasibility and performance of at-home use of a zone model predictive controller–based closed-loop insulin delivery system customized for pregnancies complicated by type 1 diabetes (CLC-P). RESEARCH DESIGN AND METHODS Pregnant women with type 1 diabetes using insulin pumps were enrolled in the second or early third trimester. After study sensor wear collecting run-in data on personal pump therapy and 2 days of supervised training, participants used CLC-P targeting 80–110 mg/dL during the day and 80–100 mg/dL overnight running on an unlocked smartphone at home. Meals and activities were unrestricted throughout the trial. The primary outcome was the continuous glucose monitoring percentage of time in the target range 63–140 mg/dL versus run-in. RESULTS Ten participants (HbA1c 5.8 ± 0.6%) used the system from mean gestational age of 23.7 ± 3.5 weeks. Mean percentage time in range increased 14.1 percentage points, equivalent to 3.4 h per day, compared with run-in (run-in 64.5 ± 16.3% versus CLC-P 78.6 ± 9.2%; P = 0.002). During CLC-P use, there was significant decrease in both time over 140 mg/dL (P = 0.033) and the hypoglycemic ranges of less than 63 mg/dL and 54 mg/dL (P = 0.037 for both). Nine participants exceeded consensus goals of above 70% time in range during CLC-P use. CONCLUSIONS The results show that the extended use of CLC-P at home until delivery is feasible. Larger, randomized studies are needed to further evaluate system efficacy and pregnancy outcomes.
A New Step in Postexposure Prophylaxis for Leprosy
Authors: David M Scollard
Journal: New England Journal of Medicine (2023)

Infection with Mycobacterium leprae is curable with a combination of dapsone, rifampin, and clofazimine (multidrug therapy), as recommended by the World Health Organization (WHO) in 1982. The use of this multidrug regimen led to an initial rapid decline in the global prevalence of M. leprae infection, a reduction that was bolstered by the removal of many previously cured patients from national registries. Encouraged, the WHO coordinated a global effort from 1990 to 2000 to eliminate leprosy as a public health problem through the use of multidrug therapy on the premise that curing new cases would interrupt transmission. Initially, this program . . .
Global Prevalence of Prediabetes
Authors: Mary R. Rooney, Michael Fang, Katherine Ogurtsova, Bige Ozkan, Justin B. Echouffo-Tcheugui, Edward J. Boyko, Dianna J. Magliano, Elizabeth Selvin
Journal: Diabetes Care (2023)

To estimate the global, regional, and national prevalence of prediabetes, defined by impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).
Emodepside for <i>Trichuris trichiura</i> and Hookworm Infection
Authors: Emmanuel C. Mrimi, Sophie Welsche, Said M. Ali, Jan Hattendorf, Jennifer Keiser
Journal: New England Journal of Medicine (2023)

Current treatments for soil-transmitted helminth infections in humans have low efficacy against Trichuris trichiura. Emodepside — a drug in veterinary use and under development for the treatment of onchocerciasis in humans — is a leading therapeutic candidate for soil-transmitted helminth infection. Download a PDF of the Research Summary. We conducted two phase 2a, dose-ranging, randomized, controlled trials to evaluate the efficacy and safety of emodepside against T. trichiura and hookworm infections. We randomly assigned, in equal numbers, adults 18 to 45 years of age in whom T. trichiura or hookworm eggs had been detected in stool samples to receive emodepside, at a single oral dose of 5, 10, 15, 20, 25, or 30 mg; albendazole, at a single oral dose of 400 mg; or placebo. The primary outcome was the percentage of participants who were cured of T. trichiura or hookworm infection (the cure rate) with emodepside 14 to 21 days after treatment, determined with the use of the Kato–Katz thick-smear technique. Safety was assessed 3, 24, and 48 hours after the receipt of treatment or placebo. A total of 266 persons were enrolled in the T. trichiura trial and 176 in the hookworm trial. The predicted cure rate against T. trichiura in the 5-mg emodepside group (85% [95% confidence interval {CI}, 69 to 93]; 25 of 30 participants) was higher than the predicted cure rate in the placebo group (10% [95% CI, 3 to 26]; 3 of 31 participants) and the observed cure rate in the albendazole group (17% [95% CI, 6 to 35]; 5 of 30 participants). A dose-dependent relationship was shown in participants with hookworm: the observed cure rate was 32% (95% CI, 13 to 57; 6 of 19 participants) in the 5-mg emodepside group and 95% (95% CI, 74 to 99.9; 18 of 19 participants) in the 30-mg emodepside group; the observed cure rates were 14% (95% CI, 3 to 36; 3 of 21 participants) in the placebo group and 70% (95% CI, 46 to 88; 14 of 20 participants) in the albendazole group. In the emodepside groups, headache, blurred vision, and dizziness were the most commonly reported adverse events 3 and 24 hours after treatment; the incidence of events generally increased in a dose-dependent fashion. Most adverse events were mild in severity and were self-limited; there were few moderate and no serious adverse events. Emodepside showed activity against T. trichiura and hookworm infections. (Funded by the European Research Council; ClinicalTrials.gov number, NCT05017194.) QUICK TAKE VIDEO SUMMARYEmodepside for T. trichiura and Hookworm Infection 02:02
A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis
Authors: Jay Tuttle, Edit Drescher, Jesus Abraham Simón-Campos, Paul Emery, Maria Greenwald, Alan Kivitz, Hyungmin Rha, Pia Yachi, Christina Kiley, Ajay Nirula
Journal: New England Journal of Medicine (2023)

Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases. Download a PDF of the Research Summary. In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses — defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains — at week 12. At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], −2.09±0.18 vs. −0.99±0.26; difference in change, −1.09 [95% confidence interval, −1.73 to −0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups. Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.) QUICK TAKE VIDEO SUMMARYPhase 2 Trial of Peresolimab for Rheumatoid Arthritis 02:02
Current policies on early detection of prostate cancer create overdiagnosis and inequity with minimal benefit
Authors: Andrew Vickers, Frank O’Brien, Francesco Montorsi, David Galvin, Ola Bratt, Sigrid Carlsson, James WF Catto, Agne Krilaviciute, Michael Philbin, Peter Albers
Journal: BMJ (2023)

Informed choice approaches lead to high rates of unsystematic PSA testing, especially among those least likely to benefit and most likely to be harmed, argue <b>Andrew Vickers and colleagues</b>
Single-Dose Rifapentine in Household Contacts of Patients with Leprosy
Authors: Le Wang, Hongsheng Wang, Liangbin Yan, Meiwen Yu, Jun Yang, Jinlan Li, Junhua Li, Yong Ning, Haiqin Jiang, Ying Shi, Wenyue Zhang, Li Xiong, Jie Liu, Yanfei Kuang, Hao Wang, Jun He, De Wang, Bin Li, Yangying Liu, Tiejun Shui, Ying Wang, Huan Chen, Xiaowei Sha, Heng Long, Xiaojin Yu, Chong Shen, Jianping Shen, Xueyuan Yang, Heng Gu, Guocheng Zhang, Baoxi Wang
Journal: New England Journal of Medicine (2023)

Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. Download a PDF of the Research Summary. We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P=0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P=0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.) QUICK TAKE VIDEO SUMMARYRifapentine for Leprosy Prophylaxis 02:04
Subendocardial Involvement as an Underrecognized LGE Subtype Related to Adverse Outcomes in Hypertrophic Cardiomyopathy
Authors: Shujuan Yang, Kankan Zhao, Kai Yang, Jialin Song, Shiqin Yu, Jiaxin Wang, Zhixiang Dong, Xuan Ma, Gang Yin, Jinghui Li, Huaibing Cheng, Minjie Lu, Xiuyu Chen, Shihua Zhao
Journal: JACC. Cardiovascular imaging (2023)
Machine Learning–Based Phenogrouping in MVP Identifies Profiles Associated With Myocardial Fibrosis and Cardiovascular Events
Authors: Olivier Huttin, Nicolas Girerd, Antoine Jobbe-Duval, Anne-Laure Constant Dit Beaufils, Thomas Senage, Laura Filippetti, Caroline Cueff, Kevin Duarte, Antoine Fraix, Nicolas Piriou, Damien Mandry, Nathalie Pace, Solena Le Scouarnec, Romain Capoulade, Matthieu Echivard, Jean Marc Sellal, Marie Marrec, Marine Beaumont, Gabriella Hossu, Jean-Noel Trochu, Nicolas Sadoul, Pierre-Yves Marie, Charles Guenancia, Jean-Jacques Schott, Jean-Christian Roussel, Jean-Michel Serfaty, Christine Selton-Suty, Thierry Le Tourneau
Journal: JACC. Cardiovascular imaging (2023)
Pre–Heart Failure Longitudinal Change in a Hispanic/Latino Population-Based Study
Authors: Toshiki Kuno, Nestor Vasquez, Ayana K. April-Sanders, Katrina Swett, Jorge R. Kizer, Bharat Thyagarajan, Gregory A. Talavera, Sonia G. Ponce, Bonnie E. Shook-Sa, Frank J. Penedo, Martha L. Daviglus, Mayank M. Kansal, Jianwen Cai, Dalane Kitzman, Carlos J. Rodriguez
Journal: JACC Heart Failure (2023)
Predicting Heart Failure With Reduced or Preserved Ejection Fraction From Health Records
Authors: Nariman Sepehrvand, Douglas C. Dover, Sunjidatul Islam, Padma Kaul, Finlay A. McAlister, Robert J.H. Miller, Nowell M. Fine, Jonathan G. Howlett, Paul W. Armstrong, Justin A. Ezekowitz
Journal: JACC Heart Failure (2023)
Utilization Rates of SGLT2 Inhibitors Among Patients With Type 2 Diabetes, Heart Failure, and Atherosclerotic Cardiovascular Disease
Authors: Aliza Hussain, David Ramsey, Michelle Lee, Dhruv Mahtta, Muhammad Shahzeb Khan, Vijay Nambi, Christie M. Ballantyne, Laura A. Petersen, Adrienne D. Walker, Waleed T. Kayani, Javed Butler, Leandro Slipczuk, Joseph G. Rogers, Biykem Bozkurt, Sankar D. Navaneethan, Salim S. Virani
Journal: JACC Heart Failure (2023)
Early Outcomes of Adult Heart Transplantation From COVID-19 Infected Donors
Authors: Shivank Madan, Marvyn Allen G. Chan, Omar Saeed, Vagish Hemmige, Daniel B. Sims, Stephen J. Forest, Daniel J. Goldstein, Snehal R. Patel, Ulrich P. Jorde
Journal: Journal of the American College of Cardiology (2023)
Management of Heart Failure–Related Cardiogenic Shock
Authors: Nikhil Narang, Vanessa Blumer, Marwan F. Jumean, Biswajit Kar, Dharam J. Kumbhani, Biykem Bozkurt, Nir Uriel, Maya Guglin, Navin K. Kapur
Journal: JACC Heart Failure (2023)
Substrates of Scar-Related Ventricular Arrhythmia in Patients With Hypertrophic Cardiomyopathy
Authors: Pietro Francia, Paula Ocaña-Franco, Ernesto Cristiano, Giulio Falasconi, Carmen Adduci, David Soto-Iglesias, Diego Penela, Matteo Sclafani, Julio Martì-Almor, Beatrice Musumeci, Camillo Autore, Antonio Berruezo
Journal: JACC. Cardiovascular imaging (2023)